Absent anti-N-methyl-D-aspartate receptor NR1a antibodies in herpes simplex virus encephalitis and varicella zoster virus infections.

PURPOSE: A 2012 report and subsequent case series described anti-N-methyl-D-aspartate receptor (NMDAR) antibodies in patients during the acute phase and relapse of herpes simplex virus 1 (HSV1) encephalitis (HSV1E). However, the prevalence of this phenomenon is unknown and systematic studies on other viral infections of the nervous system are missing. MATERIALS AND METHODS: We retrospectively analyzed serial cerebrospinal fluid (CSF) and serum samples of consecutive patients treated for neurological HSV1, HSV2 and varicella zoster virus (VZV) infections in our tertiary care university hospital between 2003 and 2013 for the presence of antibodies directed against the NR1a subunit of the NMDAR using indirect immunofluorescence. RESULTS: In total, 88 patients with the following infections were identified through an electronic database search: HSV1 (24 with encephalitis), HSV2 (6 with meningitis, 3 with encephalitis and 1 with myelitis), or VZV (3 with meningitis, 33 with encephalitis, 17 with radiculitis and 1 with myelitis). Two patients with HSV1E and HSV2E, respectively, experienced a clinical relapse. Clinical follow-up was for up to 85 months, and repetitive serum and CSF analyses for up to 43 months. However, at no time did any of the 88 patients exhibit anti-NMDAR NR1a antibodies. CONCLUSIONS: In this study, we did not detect anti-NMDAR NR1a antibodies in serial CSF and serum samples of HSV1E patients or patients with other viral infections (HSV2 and VZV). However, the presence of antibodies directed against other epitopes of the NMDAR and other neuronal cell surface antigens cannot be excluded, necessitating further studies.

The Interleukin-1 Balance During Encephalitis Is Associated With Clinical Severity, Blood-Brain Barrier Permeability, Neuroimaging Changes, and Disease Outcome.

BACKGROUND: Encephalitis is parenchymal brain inflammation, commonly due to herpes simplex virus (HSV). Key host inflammatory mediators and their relationship to blood-brain barrier (BBB) permeability, neuroimaging changes, and disease outcome are poorly understood. METHODS: We measured levels of 38 mediators in serum (n = 78) and cerebrospinal fluid (n = 37) specimens from patients with encephalitis, including 17 with disease due to HSV infection. Outcome measures were Glasgow coma and outcome scores; CSF to serum albumin ratio, reflecting BBB permeability; and, in patients with HSV infection, magnetic resonance imaging-based temporal lobe volume. RESULTS: Serum interleukin 1 receptor antagonist (IL-1RA) levels were elevated in patients with a good outcome (P= .004). Among patients infected with HSV, the ratio of CSF IL-1ß to IL-1RA was associated with a worse outcome (P= .009); a ratio of ≥0.55 pg/mL had high specificity and sensitivity for a poor outcome (100% and 83%;P= .015). Temporal lobe volume had a negative correlation with serum IL-1RA level (P= .012) and a positive correlation with serum IL-1α level (P= .0003) and CSF IL-1ß level (P= .007). A normal coma score was associated with an elevated interleukin 10 (IL-10) level in serum specimens from HSV-infected patients (P= .007) and CSF specimens from all patients (P= .016); the IL-10 level correlated inversely with BBB permeability (P= .005). CONCLUSIONS: A proinflammatory cytokine response is associated with greater clinical severity, BBB permeability, and neuroimaging damage during encephalitis. IL-1 antagonists should be investigated as adjunctive treatment in encephalitis.

Herpes simplex virus encephalitis is a trigger of brain autoimmunity.

In 5 prospectively diagnosed patients with relapsing post-herpes simplex encephalitis (HSE), N-methyl-D-aspartate receptor (NMDAR) antibodies were identified. Antibody synthesis started 1 to 4 weeks after HSE, preceding the neurological relapse. Three of 5 patients improved postimmunotherapy, 1 spontaneously, and 1 has started to improve. Two additional patients with NMDAR antibodies, 9 with unknown neuronal surface antibodies, and 1 with NMDAR and unknown antibodies, were identified during retrospective assessment of 34 HSE patients; the frequency of autoantibodies increased over time (serum, p=0.004; cerebrospinal fluid, p=0.04). The 3 retrospectively identified NMDAR antibody-positive patients also had evidence of relapsing post-HSE. Overall, these findings indicate that HSE triggers NMDAR antibodies and potentially other brain autoimmunity.

N-methyl-D-aspartate receptor antibodies in post-herpes simplex virus encephalitis neurological relapse.

Herpes simplex virus encephalitis (HSVE) is a devastating condition that relapses, often with a chorea in children, despite adequate antiviral treatment. At relapse, evidence of viral replication is frequently absent, suggesting that the relapse may be immune-mediated. Seven children who had a neurological relapse following their initial encephalitis, identified from 20 cases of pediatric HSVE, were studied. Serum and/or cerebrospinal fluid (CSF) were tested for N-methyl-D-aspartate receptor (NMDAR) and other antibodies previously reported in central nervous system autoimmunity. Five of the 7 relapsing children had choreoathetosis; 2 of these were NMDAR antibody-positive, 2 were negative (1 with HSV-positive CSF), and 1 was not available for testing. An additional patient, who relapsed with cognitive regression but with no movement disorder, was also NMDAR antibody-positive. In 2 of the NMDAR antibody-positive patients who were treated at relapse and in 1 who was treated only after 10 years of having a relapsing encephalopathy, a beneficial response was observed. Neurological relapses after HSVE may frequently be immune-mediated, particularly in children with chorea. NMDAR antibodies are common, and immunotherapy may be beneficial.

Herpes simplex encephalitis relapse with chorea is associated with autoantibodies to N-Methyl-D-aspartate receptor or dopamine-2 receptor.

BACKGROUND: Movement disorder relapses after herpes simplex virus 1 (HSV1) encephalitis have been hypothesized to be secondary to postviral autoimmunity. Recently, a proportion of patients with HSV1 encephalitis (HSE) were shown to produce autoantibodies against N-methyl-D-aspartate receptor (NMDAR). METHODS: We measured autoantibodies against NMDAR and dopamine-2 receptor (D2R) expressed at the cell surface in the stored acute serum of 9 children with HSE, 3 of whom had a relapsing course with chorea. RESULTS: The 3 patients with chorea had elevated autoantibodies against NMDAR (n = 1), D2R (n = 1), or both (n = 1), whereas patients without chorea were negative (n = 6). The prospectively identified patient with chorea and NMDAR autoantibodies improved after early treatment with steroids, intravenous immunoglobulin, and cyclophosphamide, with reduction in serum NMDAR antibody titers. CONCLUSIONS: These autoantibody findings lend support to the autoimmune hypothesis and the early use of immune suppression in post-HSE chorea.

N-methyl-D-aspartate receptor antibodies in herpes simplex encephalitis.

OBJECTIVE: To determine the presence and kinetics of antibodies against synaptic proteins in patients with herpes simplex virus encephalitis (HSE). METHODS: Retrospective analysis of 44 patients with polymerase chain reaction-proven HSE for the presence of a large panel of onconeuronal and synaptic receptor antibodies. The effect of patients' serum was studied in cultures of primary mouse hippocampal neurons. RESULTS: N-Methyl-D-aspartate receptor (NMDAR) antibodies of the immunoglobulin (Ig) subtypes IgA, IgG, or IgM were detected in 13 of 44 patients (30%) in the course of HSE, suggesting secondary autoimmune mechanisms. NMDAR antibodies were often present at hospital admission, but in some patients developed after the first week of HSE. Antibody-positive sera resulted in downregulation of synaptic marker proteins in hippocampal neurons. INTERPRETATION: Some patients with HSE develop IgA, IgG, or IgM autoantibodies against NMDAR. Sera from these patients alter the density of neuronal synaptic markers, suggesting a potential pathogenic disease-modifying effect. These findings have implications for the understanding of autoimmunity in infectious diseases, and prospective studies should reveal whether the subgroup of patients with HSE and NMDAR antibodies may benefit from immunotherapy. .

Varicella zoster virus meningoencephalitis accompanied by rhabdomyolysis without skin eruption.

We report a case of a 38-year-old man with a Varicella zoster virus (VZV) reactivation who manifested meningoencephalitis accompanied by rhabdomyolysis without a skin eruption. During the acute phase, VZV DNA was detected in serum and cerebrospinal fluid (CSF) by the polymerase chain reaction (PCR). After 16 days, all symptoms and signs resolved, and follow-up PCR studies revealed negative conversion of VZV in the serum and CSF. We discuss the possible underlying mechanism of VZV reactivation in our patient. This is the first case report of VZV reactivation meningoencephalitis accompanied by rhabdomyolysis without skin eruption demonstrated by viral DNA in the serum and CSF.

Valacyclovir for herpes simplex encephalitis.

The recommended treatment for herpes simplex encephalitis (HSE) remains intravenous acyclovir. In resource-poor countries, however, intravenous formulations are usually unavailable or unaffordable. We report the penetration of acyclovir into the cerebrospinal fluid (CSF) in patients with HSE, treated with the oral prodrug valacyclovir at 1,000 mg three times daily. The oral therapy achieved adequate acyclovir concentrations in the CSF and may be an acceptable early treatment for suspected HSE in resource-limited settings.

Steroid therapy in an infant with human herpesvirus 6 encephalopathy.

We describe a 10-month-old girl who developed convulsive status during febrile illness. Human herpesvirus 6 DNA was detected in both the serum and the cerebrospinal fluid by polymerase chain reaction. Interleukin-6 was increased in the serum. The patient improved after a commencement of steroids pulse therapy. This case suggests that proinflammatory cytokines are responsible for the pathogenesis of the encephalopathy.

West Nile encephalitis mimicking herpes encephalitis.

A male with a febrile illness, altered consciousness, and seizures was diagnosed with meningoencephalitis. The suspected etiology was herpes simplex virus on the basis of a focal seizure at presentation, and he was treated with acyclovir until this pathogen was excluded. The patient made a complete recovery. Because of a West Nile fever epidemic in Israel at the time, serology tests for West Nile virus were performed; results were positive. This case highlights the diagnostic problems in West Nile fever. The literature is discussed in brief.

Drug-induced hypersensitivity syndrome due to mexiletine associated with human herpes virus 6 and cytomegalovirus reactivation.

A 66-year-old man developed a fever of 38 degrees C and generalized pruritic rash about one month after mexiletine hydrochloride administration for ventricular tachycardia. The rash appeared as edematous erythema and papules with purpura on the lower extremities. Liver dysfunction, leukocytosis, and atypical lymphocytes were also present. Elevated antibody titer against human herpes virus 6 (HHV-6) was detected during the course of the disease (1:20 -> 1:640). The patient was diagnosed as having drug-induced hypersensitivity syndrome (DIHS) due to mexiletine. Discontinuation of the mexiletine administration and systemic corticosteroid treatment led to a temporary improvement, but tapering the corticosteroid dose twice led to recrudescence. Simultaneous with the recrudescence, elevated antibody titers against HHV-6 and cytomegalovirus were detected, as well as viral DNA in the blood, suggesting that these two viruses may have been involved in the recrudescence. The patient died of myocarditis, most likely related to cytomegalovirus. Our case indicates that, in addition to HHV-6, other herpes viruses such as cytomegalovirus can be reactivated in DIHS and may modify the clinical disease activity.

Laboratory diagnosis of central nervous system infections caused by herpesviruses.

BACKGROUND: Herpesviruses may be associated with various types of central nervous system (CNS) infections. Herpes simplex encephalitis (HSE) has to be considered one of the most severe diseases. As effective antiviral drugs are available, rapid and reliable diagnosis has become important. OBJECTIVES: To describe polymerase chain reaction (PCR) and serological methods for the detection of herpesvirus-induced CNS infections by the example of HSE. STUDY DESIGN: 620 cerebrospinal fluid (CSF) and 2400 serum samples from 2700 selected hospitalized patients with clinical suspicion of encephalitis were tested for herpes simplex virus (HSV) as well as varicella-zoster virus (VZV) DNA and HSV-specific antibodies, respectively. RESULTS: HSV-1 DNA could be detected in eight and HSV-2 in three patients with focal encephalitis. In addition, HSV-2 DNA was found in two newborns with encephalitis and two adults suffered from transverse lumbar myelitis. One VZV DNA-positive patient had developed herpes zoster accompanied by meningoencephalitis, and in the other an encephalitis without cutaneous rash was diagnosed. Intrathecal antibody synthesis could be measured when CSF was cleared from viral DNA. CONCLUSIONS: The detection of viral DNA by PCR technique has become the "gold standard" method for laboratory diagnosis of herpesvirus infections of CNS. Serodiagnosis may be useful to confirm the diagnosis retrospectively.

Acute encephalitis from 1967 to 1991.

We studied all the adult patients with acute encephalitis, 322 in all, in the Helsinki area, Finland, during the years 1967--1991. The average incidence was 1.4/100000 adults/year. The proportion of known and suggested etiologies in 5-year periods has risen from 36 (1967--71) to 59% (1987--91). Herpes simplex virus was identified most often (16%), followed by varicella-zoster (5%), mumps (4%), and influenza A viruses (4%). In addition, 20 other agents were identified. The leading cause of encephalitis in patients aged 65 years or more was varicella-zoster virus. Eighteen patients (5.6%) died. It appears that the etiology of encephalitis changes with age and with time. It is important to establish the etiological pattern, as this assists in prompt diagnosis, which is a prerequisite for successful therapy.

Neonatal herpes simplex virus infections: HSV DNA in cerebrospinal fluid and serum.

AIM: To investigate the diagnostic potential of herpes simplex virus (HSV) DNA in cerebrospinal fluid and serum; to correlate the findings with outcome in the child and with type of maternal infection. METHODS: Cerebrospinal fluid and serum specimens from 36 children with verified neonatal HSV infections, diagnosed between 1973 and 1996, were examined using the polymerase chain reaction technique (PCR). RESULTS: In 21 children for whom both cerebrospinal fluid and sera were available, HSV DNA was found in one or both specimens in 19 (90%). Overall, HSV DNA was found in the cerebrospinal fluid of 74% of 27 children, and in the sera of 20 out of 30 children (67%). In two children HSV DNA was not demonstrable in either serum or cerebrospinal fluid. In sequential specimens from four children, the persistence of HSV DNA after the end of intravenous treatment was associated with a poor prognosis. CONCLUSIONS: These findings indicate that HSV DNA detection in CSF and serum is highly sensitive for the diagnosis of neonatal HSV infections but does not replace the detection of virus in other locations using virus isolation and antigen detection.

Post-herpes encephalitic anterior pituitary insufficiency with hypothermia and hypotension.

A 49-year-old man with herpes simplex encephalitis at age 22 was admitted with hypotension (90/60 mm Hg) and hypothermia (33.7 degrees C). His blood pressure was 80-90/50-60 mm Hg, with temperatures averaging 35 degrees C, for at least 3 years before admission. Evaluation of his hypothermia and hypotension revealed a low free triiodothyronine, low normal thyrotropin, luteinizing hormone < 2 mIU/L, follicle stimulating hormone <3 mIU/L, and low testosterone of 1.39 ng/dL. A baseline cortisol of 13.9 microg/dL was stimulated to 41.8 microg/dL with corticotropin, indicating he had partial anterior hypopituitarism with an intact pituitary-adrenal axis. Posterior pituitary function was normal. MRI revealed a "bright" posterior pituitary on a T1-weighted image, further indicating a normal posterior pituitary. Extensive decreased T1-weighting on MRI in the right and left temporal lobes was consistent with encephalomalacia. With thyroid hormone replacement, his blood pressure increased to 110/70 mm Hg with a temperature of 37 degrees C.

[Herpes encephalitis at children]. / Opryszczkowe zapalenie mózgu u dzieci.

Significant mortality, high incidences of complications and permanent neurological sequel are still noted in patients suffering fro herpetic encephalitis. They result mainly from delayed diagnosis and treatment of the specific cause. The aim of our paper was the analysis o a clinical course of patients with Herpes simplex encephalitis. From 1999 to 2001 7 patients aged 2 weeks to 15 years, treated in Children' Neurology Department of Silesian School of Medicine, were diagnosed to have herpetic encephalitis. Fever, headache, vomiting, as well as alteration of consciousness, all typical for neuroinfection were main clinical symptoms present on admission. Three children presented with respiratory distress requiring admission to Intensive Care Unit. On examination "cold sores" were found in 2 patients, in remaining 5 the history of exposition to herpes labialis was obtained. On neurological examination we found either right or left hemiparesis in all patients, motor aphasia in 2 and left sided central facial nerve palsy in 1. Lumbar puncture revealed lymphocytosis in 5 patients. Anti-HSV type IgG an IgM antibodies were found in serum of all 6 patients, while only in 2 of them were detected in cerebrospinal fluid (CSF). These were the 2 most severely ill children. In 2 patients DNA HSV using PCR (polymerase chain reaction) method was found in CSF and in serum. Magnetic resonance imaging (MRI) of the head confirmed diagnosis. Although herpetic encephalitis is an uncommon, sporadic disease, the diagnosis should be considered in any child with neuroinfection and early treatment started before laboratory confirmation.

HLA-DRB1*01 allele and low plasma immunoglobulin G1 concentration may predispose to herpes-associated recurrent lymphocytic meningitis.

Recurrent lymphocytic meningitis (RLM) is a rare illness caused mostly by herpes simplex virus type 2 (HSV-2). Predisposing factors are not known. Deficiencies in immunoglobulin (Ig) G subclasses 1 (IgG1) and 3 (IgG3) and complement protein C4 are associated with susceptibility to and persistence of bacterial and viral infections. Selected HLA and mannose-binding lectin (MBL) alleles have previously been associated with recurrent genital herpes or herpetic meningitis. We assessed the frequencies of low IgG1 and IgG3, their allotypes (Gm), and HLA-A*, -B*, -DRB1*, and MBL2 alleles, as well as deficiencies in C4A and C4B genes, as potential predisposing factors for HSV-2-associated RLM. The level of IgG1 was lower (p = 0.009) and the frequency of low IgG1 was higher (p < 0.001) in patients than in controls. Furthermore, the risk for a new meningitis episode was increased in patients with low IgG1 (incident ratio 2.05). HLA-DRB1*01 (p = 0.009) and -B*27 (p = 0.050) were more common among patients than controls. We conclude that HLA-DRB1*01 and -B*27 alleles and low plasma IgG1 levels may be significant risk factors for RLM.